S270: TRANSFUSION INDEPENDENCE AFTER EXAGAMGLOGENE AUTOTEMCEL IN PATIENTS WITH TRANSFUSION-DEPENDENT ΒETA-THALASSEMIA
Authors: Franco Locatelli, Peter Lang, Selim Corbacioglu, Amanda LI, Josu De La Fuente, Donna Wall, Roland Meisel, Ami J. Shah, Robert Liem, Markus Mapara, Ben Carpenter, Janet Kwiatkowski, Maria Domenica Cappellini, Antonis Kattamis, Sujit Sheth, Stephan Grupp, Puja Kohli, Daoyuan Shi, Leorah Ross, Yael Bobruff, Christopher Simard, Lanju Zhang, Phuong Khanh Morrow, Bill Hobbs, Haydar Frangoul
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: Exagamglogene autotemcel (exa-cel) is a one-time, non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR/Cas9 gene-editing at the erythroid enhancer region of BCL11A in autologous CD34+ hematopoietic stem and progenitor cells. Aims: Evaluate efficacy and safety of exa-cel in patients (pts) with transfusion-dependent β-thalassemia (TDT) in a pre-specified interim analysis of the pivotal CLIMB THAL-111 trial. Methods: CLIMB THAL-111 is an ongoing, 24-mo, phase 3 trial of a single dose of exa-cel in pts age 12-35y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y of packed red blood cell (RBC) transfusions 2y before screening. Primary and key secondary efficacy endpoints are proportion of pts who maintained a weighted average hemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 mos (TI12; primary endpoint) and ≥6 mos (TI6; key secondary endpoint). Evaluable pts included those followed for ≥16 mos after exa-cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131. Results: As of 06 Sept 2022, 48 pts (median age 20 [range 12-35] y; 16 [33.3%] age ≥12 to <18y; 28 [58.3%] with severe genotypes [β0/β0 or β0/β0-like]) received exa-cel. Of the 27 pts evaluable for primary and key secondary endpoints, 24 (88.9%) achieved TI12 and TI6 (95% CI: 70.8%, 97.6%; P<0.0001). Pts achieving TI12 had a mean time to last transfusion of 37 (SD, 20.6) days after exa-cel infusion and remained transfusion independent (mean [range] duration 20.5 [12.1, 40.7] mos; Fig). The 3 pts not achieving TI12 had substantial reductions (70.3%, 79.6% and 95.5%) in transfusion volume from baseline. For all pts, mean total Hb was ≥11g/dL at Month 3 (≥12g/dL Month 6 onward) and mean HbF was ≥6 g/dL at Month 3 (≥ 9g/dL Month 6 onward) with pancellular distribution. Mean proportion of edited BCL11A alleles was stable over time in bone marrow CD34+ and peripheral blood nucleated cells. Pts not yet evaluable and with sufficient follow-up were also transfusion-free. Quality-of-life (QOL) measures showed clinically significant improvement from baseline: mean EQ VAS, FACT-G and BMTS scores increased by 21.0, 17.0, and 7.8 points at Month 24. All pts with sufficient follow-up achieved neutrophil and platelet engraftment (median 29 and 44 days, respectively). All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 41 (85.4%) pts had AEs of Grade 3 or 4 severity. The most common AEs were febrile neutropenia (58.3%), headache (54.2%), and stomatitis (50.0%). Most AEs and serious AEs (SAEs) occurred within first 3 mos after infusion. Two pts had SAEs considered related to exa-cel: one pt had SAEs of headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH, and another pt had SAEs of delayed engraftment and thrombocytopenia (both also considered related to busulfan). All SAEs resolved. There were no deaths, discontinuations, or malignancies. Summary/Conclusion: In this pre-specified interim analysis of the pivotal trial of exa-cel in TDT, almost all pts achieved transfusion independence, with early and sustained Hb and HbF increases, durable allelic editing, and improved QOL. Safety profile of exa-cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel can deliver a one-time functional cure for pts with TDT.Keywords: beta thalassemia, Hemoglobinopathy, Gene therapy, Clinical trial